ABSTRACT
System-wide molecular characteristics of COVID-19, especially in those patients without comorbidities, have not been fully investigated. We compared extensive molecular profiles of blood samples from 231 COVID-19 patients, ranging from asymptomatic to critically ill, importantly excluding those with any comorbidities. Amongst the major findings, asymptomatic patients were characterized by highly activated anti-virus interferon, T/natural killer (NK) cell activation, and transcriptional upregulation of inflammatory cytokine mRNAs. However, given very abundant RNA binding proteins (RBPs), these cytokine mRNAs could be effectively destabilized hence preserving normal cytokine levels. In contrast, in critically ill patients, cytokine storm due to RBPs inhibition and tryptophan metabolites accumulation contributed to T/NK cell dysfunction. A machine-learning model was constructed which accurately stratified the COVID-19 severities based on their multi-omics features. Overall, our analysis provides insights into COVID-19 pathogenesis and identifies targets for intervening in treatment.
ABSTRACT
The COVID-19 pandemic has accounted for more than five million infections and hundreds of thousand deaths worldwide in the past six months. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed inter-individual phenotypic variability. Here, we report the first host genetic study in China by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third Peoples Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe and critical ill patients after the correction of potential confounding factors. The most significant gene locus associated with severity is located in TMEM189-UBE2V1 involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We also identified that the HLA-A*11:01, B*51:01 and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial study of Chinese patients provides a comprehensive view of the genetic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host-pathogen interaction for COVID-19 and other infectious and complex diseases.
ABSTRACT
Objective To investigate the effect of intrathecal CLP257 on the bone cancer pain in rats.Methods Forty adult female Sprague-Dawley rats,weighing 180-200 g,were divided into 4 groups (n=10 each) using a random number table:sham operation group (group S),bone cancer pain group (group BCP),dimethyl sulfoxide (DMSO) group,and CLP257 group.Bone cancer pain was induced by inoculating Walker 256 mammary gland carcinoma cell suspension (about 1× 105cells) 10 μl into the medullary cavity of the left tibia.On 7th-9th days after establishment of the model,5％ DMSO 10 μl was injected intrathecally once a day in group DMSO,and 10 μg/μl CLP257 10 μl was injected intrathecally once a day in group CLP257.The mechanical paw withdrawal threshold (MWT) was measured on 1 day before establishment of the model (T0),on 1st-6th days after establishment of the model (T1-6),and at 4 h after intrathecal administration on 7th-9th days after establishment of the model (T7-9).After the last intrathecal administration,the L4-6 segments of the spinal cord were removed for determination of the expression of potassium chloride cotransporter 2 (KCC2) protein and mRNA by Western blot and fluorescent quantitative real-time polymerase chain reaction,respectively.Results Compared with group S,the MWT was significantly decreased,and the expression of KCC2 protein and mRNA was down-regulated in BCP and DMSO groups,and the MWT was significantly decreased (P＜0.05),and no significant change was found in the expression of KCC2 protein and mRNA in group CLP257 (P＞0.05).Compared with group BCP,the MWT was significantly increased,and the expression of KCC2 protein and mRNA was up-regulated in group CLP257 (P＜0.05),and no significant change was found in the parameters mentioned above in group DMSO (P＞0.05).Conclusion Intrathecal CLP257 can attenuate the bone cancer pain in rats.
ABSTRACT
Aim To investigate the changes in the ex-pression of WNK1 in spinal cord of a rat model with bone cancer pain. Methods Female SD rats, weig-hing 170 ~200 g, were randomly divided into three groups:normal control group (group C, n=3), sham operation group ( group S, n =3 ) and bone cancer pain group ( group BCP, n =24 ) . Group C was not given any treatment, and group S was injected into the bone marrow of left tibia with 5 μl PBS solution while group BCP with 5 μl WALKER 256 mammary gland cancer cell suspension (approximately 1 × 105 cells). Mechanical paw withdrawal threshold ( MWT ) was measured at d1 before inoculation ( baseline) and d3, 6,9,10,11,12 after inoculation. Group S and C were sacrificed at d 12 while group BCP at d 3 ,6 ,9 ,12 after inoculation and spinal cord ( L4~6 ) were removed at different time points for detection of WNK1 mRNA ex-pression by qRT-PCR and WNK1 protein expression by Western blot. Results Compared with group C and S,group BCP’ s MWT started to decrease since d 3 ( P0. 05 ) while the protein expression upregulated since d6 and also showed an in-creasing trend to d 12 ( P<0. 01 ) . Conclusion The expression of WNK1 in spinal cord of a rat model with bone cancer pain increased abnormally, which may be involved in the occurrence and maintenance of a rat model with bone cancer pain.
